In the context of a prospective study of recent injection drug users (IDUs) and a survey of non-injection cocaine and heroin users (NICHUs), we propose to address three major questions about hepatitis C (HCV) infection: 1) is indirect sharing (e.g., sharing cotton, cookers) a risk for incident HCV in IDUs, 2) is sharing implements for smoking/snorting drugs (e.g., straws) associated with HCV in NICHUs, and 3) because HCV clearance in uncommon (sic), what viral/host factors are associated with clearance? To address these questions, we will recruit 450 new IDUs (> 15 years old, < 1 injecting) and 200 NICHUs using outreach techniques. At baseline we will perform HCV, HIV and hepatitis B (HBV) serology and ascertain risk behaviors using audio computer assisted self-interview (ACASI); correlates of infection will be analyzed using logistic regression. IDUs will be followed at 2 month intervals with venipuncture to identify incident cases of HCV (using antibody test and HCV-PCR) and risk behaviors obtained using ACASI. In analyses, after behaviors are considered separately, a risk profile will be developed using Multiple Ordinate Risk techniques: risk factors for HCV infection will use survival methods. Clearance of HCV will be determined by HCV-PCR. Testing by viral sequence analyses and host genetic markers will be done on all new cases of HCV and comparisons between persons with persistent HCV infection and those who have cleared the virus will be done. Because HCV infection usually precedes HCV and HIV infection in IDUs study risk of infection among IDUs when they first begin to inject will provide direction for community workers to target this vulnerable population early. Additionally, this study will provide critical information in two areas that NIH Consensus Development Statement on Management of Hepatitis C identified as needing further research: 1) modes of transmission of HCV among substance abusers and 2) reasons for lack of HCV clearance.